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Matthew A. Sparks, MD: Hi. I'm Dr Matthew Sparks. Welcome to Medscape's InDiscussion series on chronic kidney disease. Today we'll be discussing focal segmental glomerular sclerosis (FSGS) with my guest, Dr Kirk Campbell. Dr Campbell is the Irene and Dr Arthur M. Fishberg Professor of Medicine at the Icahn School of Medicine at Mount Sinai and the vice chair of the Department of Medicine for Diversity, Equity, and Inclusion.
Kirk Campbell, MD: Thanks so much, Dr Sparks.
Sparks: Before we talk about FSGS, the first thing I want to ask you is how you became interested in nephrology.
Campbell: I always saw nephrology as advanced internal medicine. I felt that while pursuing nephrology training, there was added depth to my knowledge base, but I didn't lose scope of the whole body and multiple organ systems that we're compelled to have a good handle on when we're caring for patients with kidney disease. I was also really impressed with the nephrology leaders that I engaged with during medical school and residency. The folks who wrote a renal physiology textbook were certainly active in academic affairs in institution and medical school and they were nephrologists. Mentorship had a big impact on career choice in this regard.
Sparks: You've become a leader, and this is an area that has really been expanding over the past decade — FSGS and glomerular disorders in general. I always found it challenging as a medical student and resident, and even as I went through fellowship, to wrap my brain around what in the world FSGS really was. The best I can describe it is that it is a pathologic diagnosis that typically a pathologist makes. There are multiple different ways to get to that diagnosis. This makes it very challenging to treat because it's not one disease, it's multiple. Can you tell us what the evolution of FSGS is and how this has changed over the past decade or so?
Campbell: The classic teaching is that this is a histologic pattern of injury and not a disease per se, and nephrology is certainly going through a lot of revolutionary changes in this regard. When we think of membranoproliferative glomerulonephritis and membranous nephropathy, these are also conditions that are quite heterogeneous that we're getting a better appreciation for now. For FSGS, we consider it to be a histologic pattern from a number of different underlying disease causes. The collapsing form of FSGS has long been considered a distinct entity, but in the past few decades, we have identified more than 60 genes that are of monogenetic causes, not including disease modifiers and other gene noncoding variants that might affect progression of disease. We're in a position now where we can think about precision-based approaches for FSGS. The most recent practice guidelines that were published by KDIGO (Kidney Disease: Improving Global Outcomes) think of FSGS in four different categories. The primary form is one that we think of as more immunologic in its origin. There's the genetic form that I mentioned, which has been expanding in the causative gene list. Secondary etiologies include infections or medications that can cause that histologic pattern. Finally, there are undetermined causes, which we can think of as idiopathic, where we don't really know what the underlying basis is.
Sparks: Well, that's a really good way to look at the four different buckets. Before you have that diagnosis, are there any clinical features that can maybe steer you in those directions and predict what type of FSGS the individual has?
Campbell: That's really the first step in the workup. You try to see if you can find which bucket that patient belongs to. Primary FSGS classically presents with the nephrotic syndrome. This would be > 3.5 g of protein in the urine, a low serum albumin, edema, and hyperlipidemia. Those features are classically there, even before you perform a kidney biopsy. Diabetes is still the most common cause for a patient having nephrotic syndrome and nephrotic range proteinuria. You can't rule out a workup for diabetes. Certainly, we learned during the current pandemic period, screening for infection. SARS-CoV-2 is associated with the histologic pattern of injury, along with HIV and obesity. We have to think about potential contributors. But distinguishing primary vs secondary is really key. The kidney biopsy itself can be helpful in distinguishing primary vs other etiologies.
Typically, when patients have primary FSGS on electron microscopy, we tend to see really diffuse podocyte foot process effacement. Podocytes are injured across the spectrum of protein or kidney diseases. With the primary FSGS form, you tend to see diffuse effacement. That's not specific for primary. That can be a bit misleading. We again have to use our clinical judgment in defining which category the patients fall into. We also can't forget other things like congenital abnormalities (particularly in children), reflux, nephropathy, and those associated conditions. That might cause low nephron mass and a secondary FSGS feature like a solitary kidney. Imaging is important, as is using the full level of detail that we can muster in our clinical armamentarium.
Sparks: Let's take a step back and define what FSGS means. What is that pathologic diagnosis? What does it mean to have that? When a pathologist says it, what do they see?
Campbell: It's a bit intuitive when we think about it. It's focal in the sense that there's scarring in the glomeruli, but not all of them are affected. It's segmental, meaning that glomeruli that are affected aren't globally affected. There is a condition called focal global glomerulus sclerosis, where the entire glomerulus is scarred. The ones that are affected here are only a segment, a portion of each affected glomerulus that actually has a scar. It's describing the scarring pattern. One can see that it's not a very specific diagnosis, right? It's describing a histologic pattern but not getting to what's causing the scarring. We think that the scars form because you're losing podocytes and you have this misdirected filtration — the glomerular filtration barrier — and you have recruitment of inflammatory components that are also causing this milieu that leads to the scar. The point is to really get to the underlying etiology.
Sparks: You talked about the four buckets. I want to go back to that, but we want to focus on one bucket. If we've gone through and say, all right, it doesn't appear to be sort of that immunologic variation, then I would guess your patient would have pretty aggressive disease, maybe a lot of proteinuria and fast progression. You can't find any medications or infections that might be causing it, and you're kind of stuck with the genetic bucket. Right now, we have the ability to do genetic diagnoses. Who should you consider it for, and should you be doing genetic screening in patients who have FSGS with no identifiable cause?
Campbell: That's a great question. Genetic testing can be particularly useful in congenital forms. In early childhood disease onset, the yield is going to be extremely high. If a newborn has nephrotic syndrome and they're less than a year old, you're quite likely to find a disease-causing gene variant. That diagnostic yield in identifying disease-causing mutations goes down during adulthood. Deciding which adult patients would benefit from genetic testing is a topic of much ongoing discussion. We know that up to 30% of patients with steroid-resistant FSGS, for example, may have a disease-causing gene variant. I think it's most useful when you're seeing a patient with a strong family history of glomerular disease.
A good time to use genetic testing is when we are considering donor risk evaluation — for instance, if you have a potential kidney donor from a family that may have an inheritance pattern for a kidney disease. You might suspect certain types of kidney disease that the patient could progress to later on. APOL1-associated kidney disease, for example, is one that comes to mind. There is potential for precision-based therapeutics. There are clinical trials now that are enrolling patients on the basis of the results of the genetic testing, right? Precision therapeutics are being developed for some of those gene variants and their encoded proteins that we talked about earlier.
There are several reasons to consider this. We also have to remember that when patients have a genetic cause for their FSGS, they actually have a lower response to immunosuppressive treatment. You may be able to spare a lot of the potential toxicity of giving immunosuppression to patients less likely to respond.
Sparks: Let's go back to treatment, and I think that's a good segue. We talk about genetic testing and how they might not respond to some of the conventional therapies. As a nephrologist, I think this is a very challenging area. They do have clinical trials in FSGS, which I find confusing because we just talked about how it's a histologic diagnosis. How can you treat all those buckets the same? Oftentimes, there is no genetic testing in those patients, so you don't know if they had it or not. How do you, as a clinician, take these clinical trials that have been performed and then use that information to help treat patients?
Campbell: That's really important to think about — how we interpret clinical trial data. I always encourage my colleagues and trainees to look closely at inclusion criteria because that will inform what patient population may most likely benefit from the results you're getting from the trial. Most of the FSGS trials to date have not enrolled patients on criteria beyond histologic diagnosis. It's all-comers in the buckets that we mentioned. They could very well have genetic, primary, or secondary; it's a mixed bag. Even if it's stated that they would like to have patients with primary FSGS enrolled, they're often not specifically sought out or nonprimary diagnosis excluded.
We do have to be careful about how we interpret some of the data. Precision-based therapies that rely on specific genetic or molecular signatures for enrollment are important. Those will likely give us great clues as to which patients may benefit from specific therapies, like targeting TRPC6 or APOL1 mutations, for example. Those are two studies that are in progress, but then there are other agents that might benefit patients across the spectrum, in all four buckets. Whether they have primary, secondary, or genetic, we know that podocyte injury is the final common endpoint and podocyte loss for the development of those focal, segmental lesions.
There may be a therapy that would be beneficial from a podocyte protective standpoint for all patients. We may need a combination of approaches, such as precision-based as well as a general cellular-protective. That's okay, but we need to be honest and carefully interpret the data by looking carefully at inclusion criteria and really understanding what patient populations were studied.
Sparks: Can you talk about both the immunosuppressive aspects and the nonimmunosuppressive aspects of FSGS? What if you've got the diagnosis, you don't have a family history, maybe it doesn't appear to be immunologic, but maybe you can't find a causative drug to withdraw. What do you do for those patients? How do you treat them?
Campbell: A lot of it, of course, depends on the particular patient presentation, what the kidney function is like, and how preserved the kidney function is vs how close the patient may be to dialysis. Generally speaking, I believe that patients with proteinuric kidney disease, in general, benefit from renin-angiotensin system blockade. That's really been the mainstay of an effective, supportive regimen. Blood pressure control is certainly important along with low-sodium diets — all the things that we generally recommend for proteinuric kidney disorders. I know that some of my colleagues would consider adding nonsteroidal mineralocorticoid antagonists or sodium-glucose cotransporter-2 (SGLT2) inhibitors. That debate is ongoing, and a lot of great studies are ongoing as well. I typically reserve immunosuppressive therapy for patients I believe have primary disease, those patients with nephrotic syndrome. For FSGS, we know that the risk for poor outcomes and kidney function decline increases exponentially after that 3 g/d proteinuria level. I follow the current guidelines, including high-dose oral prednisone, as an initial approach.
I'm not waiting for more than 6-8 weeks for response before considering other agents like calcineurin inhibitors. A number of experimental treatment options are emerging, and some are currently out there. If patients have a contraindication to high-dose steroids, then moving more quickly to calcineurin inhibitors would be a reasonable option.
Sparks: You mentioned SGLT2 inhibitors, and we've had several discussions on this series on that. I wanted to get your opinion about some of the subgroup analyses, the one from DAPA-CKD that did not show a strong signal in that group. Why do you think that might be? Was it too small? What exactly was going on there?
Campbell: The DAPA-CKD subgroup analysis for patients with FSGS did not show a significant benefit in terms of kidney function decline or protection from kidney function decline. That was a smaller group of patients. We have more data from an efficacy standpoint for immunoglobulin A nephropathy with SGLT2 inhibitors. But again, numerous meta-analyses, including one published in The Lancet last year, showed that across the spectrum of glomerular disease, you do see a benefit. FSGS is a curious one, and again, those patients who we're talking about were a mixture of primary, secondary, genetic, and so on. Would there be a subgroup of patients with FSGS who may benefit more from SGLT2 inhibitors than others? We don't really know at this point. I always say that if the drug is safe and well tolerated, it's reasonable to consider. I certainly would love to see more of a precision-based approach for guiding our decision-making in this regard. At this point, it's a bit unclear, but there is potential benefit. I guess that is all we can say.
Sparks: Great. I'm in complete agreement. We struggle with FSGS, and you want to offer patients as many things as possible that have low side effects. This is an important consideration. That was a great overview of FSGS and where we currently are in the field. The most exciting thing is that we have a potential therapy for one of the genetic forms. I want to first talk about APOL1. Before we talk about what's happening in that space with randomized clinical trials, can you describe what is APOL1?
Campbell: It's one of the most important discoveries in the nephrology field. APOL1 stands for apolipoprotein L1. And it's really essentially a minor component of high-density lipoprotein cholesterol. It's made in the liver, but also several other tissues and, importantly, the kidney. The normal physiologic role has been widely debated and is currently being studied.
There's a circulating form of APOL1, particularly individuals with two variants of APOL1, called G1 and G2. They're resistant to this trypanosome parasite that causes African sleeping sickness, and that's quite prevalent in West Africa. Individuals with two copies of either this G1 or G2 variant, even though they're resistant to infections by the trypanosomes, they're at increased risk for nondiabetic kidney disease. A lot of work has gone into trying to better understand how these G1 and G2 variants cause kidney disease progression and why there is such a specific association in nondiabetic vs diabetic kidney disease. Again, that's still not completely understood. There's some speculation that APOL1 may act as a cation channel, and it's certainly important in innate immunity. Regardless, the risk variants account for a large burden of kidney disease in patients of West African ancestry worldwide, including the United States. Maybe about 70% of nondiabetic kidney disease in African Americans can be attributed to APOL1 high-risk alleles. It's quite an important area of study with a lot of ongoing work and attention.
Sparks: I just want to clarify for our readers: When you say "variant," do you mean that there's a mutation?
Campbell: Yes, actually, in the coding region, and that's really important to drive home.
Sparks: How hard is it for a patient to be genetically tested to see if they have this variant?
Campbell: It's a lot easier now than it has been in the past several decades. I think you've seen a proliferation of entities that offer genetic testing that's covered widely by insurance. And there are a lot of home services. We had a patient who approached us a few months ago with genetic testing results for APOL1 done on 23andMe. There are a lot of patient-directed, as well as a physician-directed, possibilities for defining APOL1 risk.
Sparks: Who typically has APOL1 mutations?
Campbell: Typically, it's a patient of West African ancestry. The epidemiology of APOL1 inheritance patterns is widely studied. We don't tend to see a lot of it in East Africa. Having one of these high-risk alleles is not sufficient to increase the risk for kidney disease. Patients need two copies to have that increased risk for kidney disease. Interestingly — incompletely penetrant — less than 30% of patients with those two high-risk alleles have kidney disease. There's clearly a second hit that's required. We speculate that it involves environmental influences, viral infections, perhaps genetic modifiers, and a number of other factors. A second hit is required to drive that phenotype and clinical presentation.
Sparks: How many individuals would have a high risk? And if you have the high-risk alleles, two of them, what's your probability of getting kidney disease?
Campbell: About 14% of African Americans are thought to have two high-risk alleles, for example, but less than 30%, maybe 25%, of those individuals actually get kidney disease. It's quite prevalent in patients of West African ancestry. The majority of patients with these two high-risk variants do not get kidney disease. It's very interesting biology.
Sparks: Most do not get kidney disease?
Sparks: What types of kidney diseases are we talking about?
Campbell: It's nondiabetic, primarily. What we used to call hypertensive kidney disease certainly would be up there. Associated kidney disease: We saw during the spring of 2020 that a number of our reports of patients with APOL1 high-risk alleles who got SARS-CoV-2 infection ended up getting a collapsing glomerulopathy. Viral infections are a big part of it, but classic FSGS is also involved. There are other conditions, reports of lupus nephritis as well, and other nondiabetic conditions have been reported.
Sparks: What if a patient listening to our podcast gets tested for APOL1 high-risk alleles and has them? They don't have kidney disease. Is there anything they can do to help prevent kidney disease?
Campbell: That comes up quite a bit, right? The majority of patients with these APOL1 high-risk alleles do not get kidney disease. I certainly would encourage a regular follow-up, trying to better understand the mechanism of kidney injury conferred by these APOL1 high-risk alleles.
There's more to come in the years ahead. For now, a regular healthy lifestyle, balanced diet, good blood pressure control, low-salt intake, and anything that's generally good for cardiovascular health is also beneficial for kidney health. Regular checkups to screen for protein in the urine and any decrease in kidney function would be important.
Sparks: There is a recent paper in The New England Journal of Medicine, which I think you are a coauthor on. Can you tell us about this? It's really exciting to see that there is a large randomized clinical trial ongoing. Where are we with this new potential new therapy?
Campbell: The drug inaxaplin targets the mutant APOL1 protein. As I mentioned, the protein may act as a channel that could promote injury. This small molecule inhibits the abnormal function of that protein in this regard and showed about a 48% decrease in proteinuria in patients with biopsy-proven FSGS in that New England Journal of Medicine manuscript. There is, as you said, a larger phase 2/3 study ongoing, which is placebo controlled — not limited to patients with FSGS but those who have proteinuric disease, regardless of histologic diagnosis or etiology. We'll get more information in the years ahead as a part of that study.
I'd also mentioned that there are other APOL1 inhibitors in clinical development. That's another small molecule again, targeting that the channel is in preclinical development. We have antisense oligonucleotides in development that could decrease APOL1 expression overall, and another study looking at the utility of baricitinib, a Janus kinase (JAK) signal transducer and activator of transcription protein (STAT) pathway inhibitor, that could be involved in that pathway and the amplification of APOL1-associated kidney injury. It's an exciting time for this precision-based approach.
Sparks: Are there any other diseases that are amplified in patients with APOL1 high-risk alleles other than kidney disease?
Campbell: APOL1 is certainly expressed in a number of different organs. That research work is ongoing. The inflammatory cascade that we're seeing certainly is amplified with patients with high-risk APOL1 alleles and has raised some attention for cardiovascular health. In the inflammatory kidney disease space and in lupus, there are some data that there might be increased risk for poor outcomes. Getting back to the heart, there is a close relationship between albuminuria, kidney function, and cardiovascular morbidity and mortality. That's certainly something that we have to pay a lot of attention to as well, going forward. We know that there is pancreatic expression in the brain and in the vasculature. There are certainly a lot of studies looking at that epidemiology going forward.
I should also mention that it's important in the transplant space in regard to kidney donors who may not have kidney disease but have high-risk APOL1 alleles. We found that donated kidney carries increased risk to a recipient. It's a lot of work, trying to better understand the risk to recipients for receiving APOL1-positive kidneys, as well as the potential risk to donors. They may be donating a healthy kidney, but also a kidney that has a high risk for APOL1 alleles being expressed. Right now, we want to do more genetic testing and carry out these studies to really have shared decision-making going forward.
Sparks: You mentioned the transplant realm and the APOLLO trial that is happening. Can you explain what the APOLLO trial is and how that might change how we look at APOL1 genetic testing and transplant?
Campbell: There's some concern for living donors who may have APOL1 high-risk alleles, but also the risk to recipients. The APOLLO study is trying to follow patients who have donated kidneys who have APOL1 and determine the outcomes among our recipients. As of now, we don't have a lot of long-term data to guide our decision-making. The APOLLO study is a multicenter study geared toward giving us some information to help in clinical decision-making for patients who are donating and receiving kidneys in the context of APOL1 with high-risk alleles being present.
Sparks: It definitely seems like a very exciting time to be in nephrology, especially in this space, with so many advances that are currently happening. Is there any last comment that you want to make to our listeners?
Campbell: As you alluded to, this is certainly an exciting time, and the best part of it is this precision-based era that we're entering. There are also studies ongoing that are using a molecular phenotyping approach through the NEPTUNE cohort to try to match patients with clinical trials that would most likely benefit them on the basis of their individual characteristics. That's a start. I think we're entering the precision medicine era in nephrology, which is, I'd say, long overdue.
Sparks: I totally agree with you. You could get a histologic diagnosis, a genetic diagnosis, and a phenotype to kind of meld together, and then offer a therapy that would be custom just for that person. It's really quite impressive. Congrats on all the work that you've done over the years to help elucidate all of these things.
Campbell: Thanks so much, Matt.
Sparks: Today we've had Dr Kirk Campbell discussing FSGS, genetic testing, and APOL1. It was a fascinating tour. Thank you so much for joining us. This is Dr Matthew Sparks for Medscape's InDiscussion series on chronic kidney disease.
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Cite this: Chronic Kidney Disease: FSGS, Genetic Testing, and APOL1 - Medscape - Sep 26, 2023.